Project Summary: The central hypothesis of this proposal is that activation of cholinergic receptors in the retina and in glaucomatous optic nerves can be used as effective neuroprotective and rehabilitative approach to mediate preservation and restoration of visual function in eyes with glaucoma. In our preliminary results we demonstrated that these mechanisms are independent from regulation of intraocular pressure. We will test this hypothesis by using cholinergic drugs in vivo by treating dogs with either topical or oral cholinergic agents that have a hereditary, slowly progressive, angle closure form of glaucoma. The broad long-term objective of this study is to evaluate the clinical efficacy and safety of cholinergic-based therapy to prevent visual loss and restore visual function in a relevant large animal model (primary canine glaucoma), which is characterized by chronic elevation of intraocular pressure and progressive retinal ganglion cell loss over the course of several years, similar to human glaucoma. Our specific aims, supported by preliminary data in dogs with a spontaneous form of glaucoma similar to humans, seek to show that topical application of an acetylcholine esterase inhibitor (demecarium bromide) and an oral cholinergic agent (citicholine) are associated with recovery of optic nerve function measured by pattern electroretinography (PERG) and the pupil light reflex, independent of intraocular pressure (IOP) regulation. Pilot data also shows demecarium bromide treatment prevents development of optic nerve head cupping (glaucomatous structural damage). We have also developed provocative intraocular pressure stress tests which reveal early functional deficits in PERG and pupil light reflex (PLR) in canine glaucomatous eyes before any structural loss of nerve fiber layer can be detected. Currently, glaucoma and ischemic disorders of the eye - including diabetes, ischemic optic neuropathy and retinal vascular occlusions - account for a significant proportion of blinding ocular diseases in veterans. Accomplishment of the specific aims in this proposal is likely to provide an additional rehabilitative approach for treatment of vision loss in veterans suffering from glaucoma and other forms of ischemia related blinding diseases. PUBLIC HEALTH RELEVANCE: Project Narrative: Ischemic insults to the retina and optic nerve caused by reduced blood flow and oxygen delivery often lead to blindness by damaging the neurons and associated glial elements of the eye. Currently, glaucoma and ischemic disorders of the eye - including diabetes, ischemic optic neuropathy and retinal vascular occlusions - account for a significant proportion of blinding ocular diseases in the veteran population. This proposal has great relevance because it seeks to demonstrate that treatment with oral and topical cholinergic agents can reverse visual dysfunction in glaucoma and also helps prevent further loss, providing an additional rehabilitative approach for treatment of vision loss in veterans suffering from glaucoma and other forms of ischemia related blinding diseases.